delta-12-oxygenated-22-isoallospirostene epoxide and process of preparing the same



United States Patent A2-12-0XYGENATED 22 ISOALLOSPIROSTENE EPOXIDE ANDPROCESS OF PREPARING THE SAME Norman L. Wendler, Linden, and Harry L.Slates, Roselle, N. 1., assignors to Merck & Co., Inc., Rahway, N. J., acorporation of New Jersey No Drawing. Original application January 8,1952, Serial No. 265,531. Divided and this application April 18, 1952,Serial No. 283,116

21 Ciaims. (Cl. zoo-239.555

This invention is concerned generally with steroid compounds and withprocesses for preparing them. More particularly, it relates to a novelprocess for the preparation of hecogenin from naturally-occurringIZ-oXygenated We have discovered that 3,8-hydroxy-12-keto-22-isoduce3a,12 dihydroxy-22-isoallospirostane 3B hydroxy 12 keto 22isoallospirostane, commonly "ice ' 2 allospirostane can be prepared byreacting 2,3-dihydroxy- 12-keto-22-isoallospirostane, commonly known asmanogenin (compound 1, hereinbelow, the radical R being keto), or2,3,1Z-trihydroxy-Z2-isoallospirostane, commonly known as agavogenin(compound 1, the radical R being hydroxy) with a hydrocarbon sulfonylchloride to produce the corresponding 2,3-bis(hydrocarbon-sulfonoxy)-12-oxygenated-22-isoallospirostane compound (compound 2), reacting thelatter compound with an alkali metal iodide to produce the correspondingA -12- oxygenated-22-isoallospirostene compound (compound 3), reactingsaid A -12-oxygenated-22-isoallospirostene compound with perbenzoicacid, or other organic peracid, thereby forming the corresponding2,3-epoxy-l2- oxygenated-ZZ-isoallospirostane compound (compound 4),reacting this epoxide with a reducing agent to pro (compound 5),reacting said- 3a,12-dihydroxy-22-isoallospirostane With chromic acid toform 3,12-diketo-22-isoallospirostane, commonly known as hecogenone(compound 6), reacting the latter compound with a reducing agent to form35,12-dihydroxy-22-isoallospirostane, commonly known as rockogenin(compound 7), reacting said 3,3,12- dihydroxy-22-isoallospirostane withapproximately one equivalent of an acylating agent thereby selectivelyacylating the 3,3-hydroxy group and forming 3p-acyloxy-12-hydroxy-Z2-isoallospirostane (compound 8), reacting this compound withchromic acid to form 3fi-acyloxy-12- keto-22-isoallospirostane (compound9), and reacting the latter compound with a hydrolyzing agent to produceknown as hecogenin (compound 10).

'The reactions indicated hereinabove may be chemically represented asfollows:

NaI l I acetone l I 1 Compound 3 B0 I nlsoioi B15020 l HO- B18020 i l 1Compound 1 Compound 2 g a 1 Reducing O agent;

Compound 4 Compound 5 l v d I Y I I Chromlc I I 255 O a Compound 6Partial acylatlon Compound 7 Compound 10 In. the foregoing formulae, Ris a keto or hydroxy 3U radical, R2 is acyl, and R], is an alkyl, arylor aralkyl radical.

As starting materials in carrying out our novel process We can employthe free, naturally-occurring 2,3-dihydroxy-lZ-keto-(orhydroxy)-allo-sapogenins (wherein rings A and B are in the so-calledtrans configuration, i. e. the connection of the rings is such that the-10 methyl group and the hydrogen atom are trans with respect to theplane formed by ringv A) which can be obtained from agave plants asdescribed in I. A. C. S. 69, 2167 (I947). Suitable starting materialsinclude the pure sap'ogenins manogenin (2,3-dihydrQXy-lZ-keto22-isoallospirostane) and agavogenin (2,3-dihydroxy-l2-hydroxy-22-isoallospirostane) instead of starting with the puresapogenin, we canalso employ crude mixtures of. these sapogenins containing the corresponding A -dehydro-manogenim 2,3- dihydroxy l2 keto9,11 dehydro 22 isoallospirostane (compound 11 hereinbelow) and A-dehydroagavogenin, 2,3 dihydroxy 12 hydroxy 9,11dehydro-22-isoallospirostane (compound 12) which may be structurallyrepresented asfollows:

Compound 12 Compound 9 Hydrolyzlng 1 agent Where a mixture of thesapogerrin and its n -dehydroderivative- (that is a mixture of the2,3-dihydroxy-l2- oxygenated-isoallospirostane and A -ZJ-dihydrOXy-IZ-oxygenated-22-isoallospirostene) is employed as the starting material,the crude mixture is reacted directly with a hydrocarbon sul'fonyl'chloride to produce a mixture containing the corresponding2,3-bis(hydrocarbonsulfonoxy)-12roxygenated-22-isoallospirostanecompound and n -2,3-bis (hydrocarbon-sulfonoxy)-l2-oxygenated-22-isoallospirostene compound. The mixture thus formed is reacted withan alkali metal iodide thereby producing a mixture containing thecorresponding A 12- oxygenated-ZZ-isoallospirostene compound admixedwith the A -12-oxygenated-22-isoallospirostadiene compound. This mixtureis reacted with metallic sodium and a lower alkanol, such as butanol,thereby reducing the n -double bond of the A-12-oxygenated-22-isoallospirostadiene compound without substantiallyaffecting. the unsaturated linkage attached to the carbon atom in the2-position of the molecule, to producea reduction product containing, asessentially the sole component, A -12-hydroxy- 22-isoallospirostene.(-The sodium-allianol reduction also converts the l2-keto functionalgroup, if originally present, to the l2-hydroxy group under theconditions used to saturate the 9-11 bond of the n -unsaturatedcomponent of the mixture.)

In carrying out our novel procedure, the 2,3 dihydroxyl2-oxygenated22-isoallospirostane compound, such as 2,3- dihydroxy-E2keto-22-isoallospirostane, 2,3,12-trihydroxy- 22-isoallospirostane andthe; like, or a mixture of said2,3-dihydroxy-lZ-oxygenated-ZZ-isoallospirostane andthe corresponding A-2,3 dihydroxy 12 oxygenated 22 isoallospirostene compound such as A-2',3-dihydroxy-12- keto-22-isoallospirostene, A-2,3,12-trihydroxy-22-isoallospirostene and the like is brought intocontact with a hydrocarbon sulfonyl chloride, as for example, an alkanesulfonyl chloride such as methane sulfonyl chloride, ethane sulfonytchloride, an aryl sulfonyl chloride such as benzene sulfonyl chloride,p-toluene sulfonyl chloride, an aryl-substituted alkane sulfonylchloride such as phenylmethane sulfonyl chloride, and the like. Thisreaction is conveniently conducted by bringing the reactants together insolution in a tertiary amine such as pyridine. The tertiary amine ispreferably anhydrous, and the tem perature of the reaction mixture isordinarily maintained within the range of about 0-5 C. Under thesereaction conditions the acylation reaction is substantially complete inabout 24 hours. Where the starting material employed. in the reactioncontains a l2-hydroxy substituent, as in2,3,l2-trihydroxy-22-isoallospirostane or (sf-2,3,12-trihydioxy-22-isoallospirostene, we ordinarily utilize substantially twomolecular equivalents of hydrocarbon sulfonyl chloride to one molecularequivalent of the 2,3, 12- trihydroxy-22-isoallospirostane or A -dehydroderivative, whereby the hydroxy substituents attached to the C-2 and 0-3carbon atoms are preferentially esterified (sulfonated) and reaction ofthe 12-hydroxy grouping with the hydrocarbon sulfonyl chloride isminimized.

In accordance with this procedure, there is obtained, Where puremanogenin or agavogenin is utilized as the starting material thecorresponding2,3-bis(hydrocarbonsulfonoxy)-12-oxygenated-22-isoallospirostane such as2,3 bis(methane sulfonoxy) 12 keto 22 isoallospirostane,2,3-bis(benzene-sulfonoxy)-12-keto-22-isoallospirostane,2,3-bis(p-toluene-sulfonoxy)-12-keto-22-isoallospirostane,2,3-bis(methane-sulfonoxy)-12-hydroxy- 22-isoallospirostane,2,3-bis(benzene-sulfonoxy)-12-hydroxy-22-isoallospirostane,2,3-bis(p-toluene-sulfonoxy)- 12-hydroxy-22-isoallospirostane; where amixture of the pure sapogenin and its A -dehydro derivative is utilized,the product of the reaction with the hydrocarbon sulfonyl chlorideconsists of a mixture of the 2,3-bis(hydrocarbon sulfonoxy) 12oxygenated 22 isoallospirostane (such as the compounds enumeratedhereinabove) and the corresponding A -2,3-bis(hydrocarbonsulfonoxy) 12oxygenated 22 isoallospirostene, such as A-2,3-bis(methane-sulfonoxy)-12-keto-22-isoallospirostene, A-2,3-bis(benzenesulfonoxy)-12-keto-22 isoallospirostene, A-2,3-bis(p-toluene-sulfonoxy) -l2-keto-22-isoallospirostene, A 2,3bis(methane sulfonoxy) 12 hydroxy 22 isoallospirostene, A 2,3bis(benzene sulfonoxy 12 hydroxy 22 isoallospirostene, A 2,3 bis(ptoluene sulfonoxy) 12 hydroxy 22 isoallospirostene, and the like. 7

The reaction between the sodium iodide and the 2,3- b is(hydrocarbonsulfonoxy) 12 oxygenated 22 isoallospirostane compounds, or betweensodium iodide and mixtures of these 2,3-bis(hydrocarbon-sulfonoxy)-12-oxygenated-22-isoallospirostane compounds and their A9-dehydroderivatives, is carried out by bringing the reactants together inacetone solution, preferably at a temperature of about 100 C., underwhich conditions the elements of the hydrocarbon sulfonic acid areeliminated from the molecule to give the corresponding A -l2-oxygenated-22-isoallospirostene compound such as A -12-keto-22-isoa1lospirostene, A -12-hydroxy-22-isoallospirostene, and thelike; where a mixture of2,3-bis(hydrocarhon-sulfonoxy)-12-oxygenated-22-isoall0spirostanecompound and its A -dehydro-derivative is reacted with sodium iodide theproduct is the corresponding A -12-oxygenated-Z2-isoallospirosteneadmixed with A -12-oxygenated-22-isoallospirostadiene such as A-12-keto-22- isoallospirostadiene, A-12-hydroxy-22-isoallospirostadiene, and the like.

As set forth hereinabove, where a mixture of the A-12-oxygenated-isoallospirostene compound and the corresponding A-l2-oxygenated-22-isoallospirostadiene compound is obtained inaccordance with the foregoing procedure, this mixture is reacted withmetallic sodium in a lower alkanol such as butanol, preferably at thereflux temperature, whereby the A -double bond in the A42-oxygenated-22-isoallospirostadiene component of said mixture isreduced without substantially affecting the unsaturated linkage attachedto the carbon atom in the 2-position of the molecule to produce A-l2-hydroxy-22- isoallospirostene. Under these conditions any nuclearketo radicals present in the molecule are converted to the correspondinghydroxy grouping. For example, the sole final product obtained byapplying this treatment to A -1Z-keto-22-isoallospirostene, A-12-hydroxy-22-isoallospirostene, A -12-keto-22-isoallospirostadiene andA l2-hydroxy-22-isoallospirostadiene or mixtures thereof is Al2-hydroxy-22-isoallospirostene.

These A -l2-oxygenated-22-isoallospirostene compounds such as A-l2-keto-l-2-isoallospirostene, A -12-hydroxy-22isoallospirostene, andthe like (whether obtained utilizing pure manogenin or agavogenin asstarting materials or whether obtained utilizing as starting substancesthese sapogenins admixed with their A -de hydro derivatives), are thenreacted with an organic peracid such as perbenzoic acid, perphthalicacid, andthe like. The reaction between the A-12-oxygenated-22-isoallospirostene and the organic per-acid isordinarily carried out by bringing the reactants together in solution ina non-oxidizable organic solvent such as benzene, chloroform, and thelike, preferably at a temperature within the range of O10 C., therebyforming the. corresponding 2,3-epoxy-l2-oxygenated-22-isoallospirostanecompound such as 2,3-epoxy-l2-keto-22-isoallospirostane,2,3-epoxy-12-hydroxy-22-isoallospirostane, and the like. The 2,3 epoxy 112 oxygenated 22, isoallospirostane compound is then reacted with areducing agent, preferably lithium aluminum hydride, whereby the 2,3-epoxy substituent is converted to a 3a-hydroxy grouping and, at the sametime, any nuclear keto radicals present in the molecule are converted tothe corresponding hydroxy grouping. Thus, irrespective of whether2,3-epoxylZ-keto-22-isoallospirostane or 2,3-epoxy-l2-hydroxy-22-isoallospirostane is utilized in the reaction with lithium aluminumhydride, the product obtained is the 3:1,12-dihydroxy-22-isoallospirostane. The reduction procedure is ordinarilycarried out by intimately contacting the2,3-epoxy-12-oxygenated-22-isoallospirostane compound and the reducingagent in a liquid medium; where lithium aluminum hydride is used as thereducing agent, the reaction is preferably conducted in either solutionand at a temperature within the range of about 2540 C.

Although the 3a,12-dihydroxy-22-isoallospirostane pro duced inaccordance with the foregoing reduction proce dure may be isolated inpure form if desired, we ordinarily react the crude3a,12-dihydroxy-22-isoallospirostane with an oxidizing agent such aschromic acid, thereby producing 3,12-diketo-22-isoallospirostane,commonly known as hecogenone. The reaction between the crude3a,l2-dihydroxy-22-isoallospirostane and the chromic acid is conductedby intimately contacting the reactants in a non-oxidizable liquidmedium, such as acetic acid, preferably at a temperature of about 25 C.Under these conditions the oxidation reaction is ordinarily complete inabout thirty minutes. The hecogenone thus produced is recovered from thereaction mixture (after destroying any excess oxidizing agent which maybe present) by evaporating the solvent, and the crude residualhecogenone is purified by recrystallization from an organic solvent suchas ether.

The 3,12-diketo-22-isoallospirostane (hecogenone) is then reacted with areducing agent, such as lithium aluminum hydride, utilizingsubstantially the same reaction conditions as those describedhereinabove in connection with the reduction of the2,3-epoxy-l2-oxygenated-22- isoallospirostane compound, thereby forming3,9,12-dihy droxy-22-isoallospirostane.

The latter compound is then subjected to a partial acylation reaction,preferably utilizing as the acylating agent succinic anhydride inpyridine, to form the corresponding3fi-acyloxy-12-hydroxy-22-isoallospirostane compound such as 38-(ti-carboxy-propionoxyyl2-hydroxy-22-isoallospirostane, and the like.The latter compound is then reacted With an oxidizing agent, such aschromic acid in acetic acid (utilizing substantially the same reactionconditions as those employed hereinabove for the oxidation of the3a,1Z-dihydroxy-22-isoallospirostane), thereby producing thecorresponding 3 3-acyloxy- 12-keto-isoallospirostane such as3;3-(/3-carboxy-propionoxy) -12-keto-22-isoallospirostane.

The 3B-acyloxy-l2-keto-22-isoallospirostane is then reacted with asaponifying agent, such as an aqueous solution of an alkali metalhydroxide. It is ordinarily preferred to conduct the saponification byheating an aqueous methanol solution containing potassium hydroxide andthe 3fi-acyloxy-l2-keto-22-isoallospirostane compound under refluxthereby forming the desired 3fi-hydroxy-l2-keto- ZZZ-isoallospirostane,commonly known as hecogenin. The hecogenin is conveniently recovered byevaporating the hydrolysis solution to dryness, the residual crudehecogenin is readily purified by extracting the residue with chloroform,washing the chloroform solution with water, and crystallizing the crudeproduct from a mixture of chloroform and ethyl acetate.

The following examples illustrate methods of carrying out the presentinvention but it is to be understood that these examples are given forpurposes of illustration and not of limitation.

Example 1 Ten grams of dry 2,3-dihydroxy-12-keto-22-isoallospirostane,commonly known as manogenin, was dissolved in cc. of anhydrous pyridine,and 10 cc. of methane sulfonyl chloride was added to the resultingsolution while maintaining the temperature within the range of 0-5 C.The resulting mixture was allowed to stand at a temperature of 0 to 5 C.fora period of about twentyfour hours, and the reaction product was thenpoured into ice-water. The solid material which crystallized from theaqueous mixture was recovered by filtration, washed several times withwater and dried. The dry material was recrystallized from acetone-ethylacetate to give 11 g.

"7 of crystalline 2;-3bis(.rnesyloxy)-.l2-keto-22-isoallospirostane; .M.P. 241-242 C. .dec. Analysis.?Calc.-d for C29H4609S2: -C, 57.81; H,7.64; S, 10.63. Found: C, 57.93;;1-1, 7.5238, 10.71.

Example 2 Six grams of 2,3-bis(rnesyloxy)-12-keto-22-isoallospirostaneand 25 g. of sodium iodide were dissolved in 300 cc. of acetone and thesolution was heated at a temperature of about 100 C. in a closed vesselunder pressure for a period of about seventeen hours. The reactionmixture was then filtered thereby removing the precipitated sodiummethane sulfonate by-product and the latter was washed with copiousportions of acetone. The acetone mother liquor and washings Werecombined and the acetone evaporated therefrom in vacuo. The residualmaterial was dissolved in ether-chloroform and the re sulting solutionwas washed free of iodine with 2% aqueous sodium thiosulfate solution.The organic layer was dried over anhydrous sodium sulfate, evaporated todryness, and the residual material was recrystallized from acetone togive 2.9 g. of A -l2-keto-22-isoallospirostene; M. P. l-99 200 C.Analysis.Calcd for Carl-14003: C, 78.59; H, 9.77. Found: C, 78.54; H,9.75.

Example 3 Eight and two-tenths cubic centimeters of a benzene solutionofperbenzoic acid (0.33 millimole per cc.) was added to a solution of 1g. of A -12-keto-22-isoallospirostene in 10 cc. of benzene. Theresulting mixture was allowed to stand at a temperature of about l0 C.for a period of about forty-eight hours. The reaction solution wasdiluted to four times its volume with ether, and the resulting etherealsolution was washed free of excess perbenzoic acid with cold aqueoussodium carbonate solution. The washed ethereal solution was dried,evaporated to dryness, and the residual material was recrystallized fromether-petroleum ether to give 0.60.7 g. of,3a-epoxy-l2-keto-isoallospirostane; M. P. 210-213" C. Analysis.Calcdfor Carl-14004: C, 75.70; H, 9.41. Found: C, 76.02; H, 9.35.

Example 4 One gram of 2a,3ot-epoxy-12-keto-22-isoallospirostane wasdissolved in 35 cc. of anhydrous ether, and the solution was added, withstirring to a solution of 200 mg. of lithium aluminum hydride in 70 cc.of ether, while maintaining the temperature of the mixture at about C.The resulting solution was stirred at a temperature of .about 25 .C. foran additional period of forty-five minutes, and then at the refluxtemperature of the ether solution for a five minute period. Thereactionmixture was cooled to a temperature of about 0 C. and aqueoushydrochloride acid was added to the cold reaction mixture to decomposeunreacted lithium aluminum hydride. The ethereal reaction solution wasseparated from the aqueous layer, washed with water, and dried overanhydrous sodium sulfate. The dry ethereal solution was then evaporatedto give approximately 1 g. of crude 3a,l2-dihydroxy-,22-isoallospirostane which was obtained in the form of an amorphouspowder.

One gram of crude 3a-1Z-dihydroxy-22-isoallospirostane was dissolved in125 cc. of acetic acid and to the solution was added a solution of 750mg. of chromic acid anhydride in 50 cc. of 80% aqueous acetic acid. Theresulting mixture was allowed to stand at a temperature of about 25 C.for a period of about thirty minutes. Sufficient methanol was added tothe reaction mixture to destroy the excess oxidizing agent, and thesolvents were evaporated from the solution in vacuo. The residualmaterial was extracted with ether, and the ether solution was washedthoroughly with 10% aqueous sodium hydroxide solution thereby removingacidic materials. The ethereal solution was then dried and the etherevaporated therefrom to give 0.49 g. of 3,l2-diketo-22-isoallospirostane(commonly known as hecogenone) which was obtained in the form of smallcolorless needles; M. P. 238-2415 C. Analysis.-Calcd for CnwHm uz C,75.70; H, 9.41. Found: C, 75.44; H, 9.09.

Example 5 To a solution of 1.5 g. of lithium aluminum hydride in 100 ml.of dry ether was added dropwise, with stirring, a solution of 1.7 g. of3,12-diketo-22-isoallospirostane (hecogenone) dissolved in 75 ml. ofanhydrous tetrahydrofuran. The reaction mixture was stirred for twohours at room temperature, and the excess lithium alumis mhydridewas-dec mp dfi st wi h i e water au lilsn wi h i -01d dilut aqu os hy ochloric ci olution- The organic layer was separated, washed withmatter, dried-andtbe solvents evaporated therefrom togive 313,1 2:dihydroxy 22-iso l1ospirostame which was o ain d i th form of ,an oilyresidue which crystallizedon standing; M. P. 198-202 C.

The crude 35,12-dihydroxy-22-isoallospirostane prepared as describedabove was dissolved in 20 ml. of anhydrous pyridine, treated with 3 g.of succinic anhydricle, and-the mixture heated at a temperature of fortwo or three hoursin a nitrogen atmosphere. At the end of this period,.the pyridine was evaporated from-the solution in vacuo, and theresidual materialwas extracted with water and chloroform. The chloroformlayer was extracted with dilute aqueous hydrochloric acid, washed withwater, dried over sodium sulfate and evaporated to d yn to give 2. gof rde educa ion-p omotion)- l2-hydroxy-22-isoallospirostane.

A solution of the-cr e 35- (fi-carboxypmp o oxy):1 hydroxy- ,2-isoal1spir stan (pr par d as des ri ed above) in 60 ml. of ace i cid conta nin325 msof chromic acid was allowed to stand at a temperature of about 25C. for aperiod of about fifteenhours. Sufficient methanol was added tothe reaetion mixture do p se x ss chr mic id, an th s vents wereevaporated from the resulting mixture in vacuo. The residual materialwas dissolved in chloroformeether, and the organic layer was washed withwater, dried over anhydrous sodium sulfate, and evaporated to dryness;to give 2.16 g. of crude (fi-carboxy-propionoxy)- l21keto-22-isoallospirostane. The crude 3fi-(fl carboxy-propionoxy)a 12-keto22-isoallospirostane was dissolved in -50 ml. of methanol, a solution of4 g. of potassium hydroxide in .Sce. of water was added to themethanolic solution, andthe resulting mixture was heated under refluxfor a period of about fourhours in a nitrogen atmosphere. The solventswere evaporatedfrom the reaction solution in vacuo, and the residualmaterial was-extracted with chloroform. The chloroform solution waswashed with water until neutral, dried and evaporatedto dryness. Theresidual crystalline material was crystallized from chloroform-ethylacetate to give substantially pureSB-hydroxy-12-keto-22d5ot1llospirostane, commonly known as hecogenin,which was obtainediin the form of silvery plates or prisms; P.'2 63-264C.

Example '6 period of about twenty-four hours, and the reaction prodnotwas then poured into ice-water. The solid material which crystallizedfrom the aqueous mixture was recovered by filtratiomwashed several timeswith water and dried. The dry material was recrystallized fromacetoneethyl acetate to give about 10 g. of a mixture of 2,3-bis-(mesyloxy)-12-keto-22-isoallospirostane and A -2,3-bis- (mesyloxy) lZ-keto 22-isoallospirostene.

Example 7 Six grams of a mixture of 2,3-bis(mesyloxy)il2eketo-22-isoallospirostane and A -2,3-bis(mesyloxy-)-12-keto-22-isoallospirostene (prepared as described in Example 6), and 25 g. ofsodium iodide were dissolved in 300cc. of acetone, and the solution washeated at a temperature of about 100 C. in a closed vessel underpressure for a period of about seventeen hours. The reaction mixturewasthen filtered thereby removing the precipitated sodium methanesulfonate by-product and the latter was washed with copious portions ofacetone. The acetone mother liquor and washings were combined, and theacetone evaporated therefrom in vacuo. The residual material wasdissolved in ether-chloroform, and the resulting solution was washedfree of iodine with 2% aqueous sodium thiosulfate solution. The organiclayer was dried over anhydrous sodium sulfate, evaporated to dryness,and the residual material was recrystallized from acetone to give about3 grams of a mixture of A -l2-keto-22-isoallospir0stene and 4 9.712.:keto-22-isoallospirostadiene.

Example 8 About 3 grams of a mixture of A -12-keto-22-isoal1ospirostene,and-A -1Z-keto-22-isoallospirostadiene (prepared as described in Example7 hereinaboive) were dissolved in 500 cc. of n-butanol. The resultingsolution was heated at the reflux-temperature, and 15 g. of metallicsodium were added portion-wise to the solution at a rate so as tomaintain a vigorous reaction. After all of the sodium had reacted, 200ml. of Water was added to the reaction solution and the butanol' wasevaporated from the aqueous butanol solution in vacuo. The residualaqueous slurry was filtered and the crystalline product dried to give A-l2-hydroxy-22-isoallospirostene substantially free of the A-dehydro-derivative.

This product was converted to Bfi-hydroxy-lZ-keto-ZZ- isoallospirostane(hecogenin) in accordance with the procedure described in Examples 3, 4and 5 hereinabove.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of our invention.

1. The process which comprises reacting a2,3-bis(hydrocarbon-sulfonoxy)-12-oxygenated-22- isoallospirostanecompound having the formula:

wherein R is anjoxygen-containing radical selected from the group whichconsists of keto and hydroxy radicals and R1 is a hydrocarbonsubstituent,'with an alkali metal iodide to form the corresponding A-12-oxygenated-22-isoallospirostene compound having the formula:

wherein R is an oxygen-containing radical selected from the group whichconsists of keto and hydroxy radicals,

and reacting this compound with an organic per-acid to produce thecorresponding 2,3-ep'oxy-l2-oxygenated-22- isoallospirostane compoundhaving the formula:

wherein R is an oxygen-containing radical selected from a the groupwhich consists of keto and hydroxy radicals.

'2. The process'which comprises reacting a 2,3-bis-(hydrocarbon-s'ul'fonoxy)-12-oxygenated-22- isoallosp irostanecompound having the formula:

B15020 I B 5010 wherein R is an oxygen-containing radical selected fromthe group which consists of keto and hydroxy radicals and R1 is'ahydrocarbon substituent, with sodium iodide in a medium comprisingacetone to form the corresponding 5 A-12-oxygenated-22-isoallospirostene compound having the formula:

wherein R is an oxygen-containing radical selected from the group whichconsists of keto and hydroxy radicals, and reacting this compound withperbenzoic acid to produce the corresponding2,3-epoxy-12-oxygenated-22-isoallospirostane compound having theformula:

wherein R is an oxygen-containing radical selected from the group whichconsists of keto and hydroxy radicals.

0 3. The process which comprises reactiong a 2,3-bis-(hydrocarbon-sulfonoxy)-12 keto 22 isoallospirostane compound having theformula:

wherein R1 is a hydrocarbon substituent with an alkali metal iodide toform A -12-keto-22-isoallospirostene having the formula:

and reacting this compound with an organic per-acid to produce2,3-epoxy-12-keto-22-isoallospirostane having the formula:

0: l V i 11 4. The process which comprises reacting 2;3 bis(mesylo'xy)12=leto-22 isoallosgifostanehavinggtheformula:

OHtBOaO CHISOQO with sodium iodide in a mediumcomprising acetone toprolduce AP-lZ-keto-22-isoal1osp1rostene having the formu a:

and reacting this compound with perhenzoic acid to produce2,3-epoxy-1Z-keto-22-isoa1lospirostane having the formula:

5. The process which comprises reacting an alkali metal iodide with amixture containing a 2,3-bis(hydrocarbon-sulfonoxy)-l2-oxygenated 22isoall'ospirostane compound having the formula:

wherein R is an oxygen-containing radicalt selected from the group whichconsists of keto and hyfiroxy radicals and R1 is a hydrocarbonsubstituent, and Ethe corresponding A-2,3-bis(hydrocarbon-sulfonoxy)w12:oxygenated-22- isoallospirostenecompound having the formula:

wherein R is an oxygen-containing radical selected from the group whichconsists of keto jand hydroxy radicals and R1 is a hydrocarbonsubstit'lient to form a mixture 12 of; the corresponding A -12oxygenated 2f isballospiro stene cornppz'mmt?havingthe formula:

la l a .t I

wherein R is an oxygen containing radical-selected from the-group whichconsists of ketoand' hydfpxy: radicals and the correspondingA3 l2oxygenated-22 isoailospirostadiene compound having theformula':

wherein R is an oxygen-containing*radical selected from the groupwhichconsistssofr hate. and hydroxy radicals, reacting: thelattermixture with metallic sodiumin; a medium. comprising; a: lower--aliphaticalcohol, therelgy forming, astthef sole reaction. product--A-12-hydroxy1-22F iso allos pirostene liavingrthe -frmuia:

' andmeactingtsaidi A 12-hydroxy;22 isoallspirostene with arpor-ganic--per-acidtto. produce 2,3-epoxy-12 hydroxy22-isoallospiros'tane=havingzthe'iormulaz 6. The process which comprisesreactiiig' amiiitui'e" of g, 3-b si(rnesyldxy)124mm-22-iscsa11epirostane havingnhe ormu a:

CHISOaO GHaSOaO '13 and A -2,3-bis (mesyloxy) -12-keto 22isoallospirostene having the formula:

CHaBOaO I OHaSOzO I with sodium iodide in a medium comprising-acetone toform a mixture of A -l2-keto-22-isoallosp1rostene having the formula:

l l I v and1 A -12-keto-22-isoallospirostadiene having the formu a:

reacting this mixture with metallic sodium in butanol, therebyconverting both components of said mixture to A-lZ-hydroxy-22-isoallospirostene having the formula:

and reacting said A -12-hydroxy-22-isoallospirostene with perbenzoicacid to produce 2,3-epoxy-12-hydroXy-22-iso- 1 allospirostane having theformula: v v r l t i 14 7. The process which comprises reacting a 2,3-bis(h y* drocarbon-sulfonoxy) -12-oxygenated-22- isoallospirostanehaving the formula:

whereinvR is an oxygen-containing radical selected from the group whichconsists of keto and hydroxy radicals and R1 is a hydrocarbonsubstituent-with an alkali metal iodide to form the corresponding A-l2-oxygenated-22-isoallospirostene compoundhaving the formula:

wherein R is an oxygen-containing radical selected from the group whichconsists of keto and hydroxy radicals.

The process which comprises reacting a 2,3-bis (hydrocarbon sulfonoxy)12 oxygenated-ZZ-isoallospirostane compound having the formula wherein Ris an oxygen-containing radical selected from the group which consistsof keto and hydroxy radicals and R1 is a hydrocarbon substituent withsodium iodide in a medium comprising acetone to form the corresponding A-12-oxygenated 22-isoallospirostene compound having the formula:

wherein R is an oxygen-containing radical selected from the group whichconsists of keto and hydroxy radicals.

9. The process which comprises reacting a 2,3-bis(hydrocarbon sulfonoxy)12 keto-22-isoallospirostane compound having the formula:

2,695,288 1:5 whrinf R1 is;zi,.hydro ca1rhon suhstituentwith an alkali 12 f1'l1 e process which comprises reacting A -12-ketometal: iodid'toform A -12-keto-22-isoallospirostene hav- 22-i'soa1lospiros'tene' havingthe formula: ing the formula:

1'6 'fh pl-pcpess 'hj' 'h gmb g sfgq ngz;gqfiflmgsyp with perbenzoicacid to produce 2,3-epoxy-12-keto-22-is0- oxy)12-keto-22-isoa1lospirostane having the formula: flllospllostane havmg-The formula;

OHxBOnO CHaSOzO with sodium iodide in a medium comprising acetone toproduce A 12-keto-22-isoallospirostene having theformulaz 13. A compoundselected from the group which conmula:

11. The process which comprises reacting wA-lz-oxygenaiedn'lsoauosplmstene compomd having the wherein R is anoxygen containing radical selected from milk: the group which consistsof keto and hydroxy radicals attached to the C 1 2 carlqonatorns andepoxides thereof 1 4; A :22'-iscs11ospimtehe compounds having theformula:

wherem R is an oxygen-containing radical; selected from i i thegroupwhich consists of keto and hydroxy radicals with i an organicper-acid to produce the corresponding 2,3-epoxy-12-oxygenated-22-isoallospirostane compound having-theformulai 7whereln R is an oxygen containing radical selected from thegroupwhiclizconsists of'keto and 'hydroxy radicals attachd' to' the;C-l-Zcarbon atom. I

15. 13 -12 keto-22-isoailosp1rostene hax ingthe formula:

wherein R is an oxygen-containing radical selected from the group whichconsists of keto andhydroxyradlcals.

sists of A -22-isoallospirostene compounds having the for- 17 16. A-l2-hydroxy-2Z-isoallospirostene having the forwherein R is an oxygencontaining radical selected from the group which consists of keto andhydroxy radicals attached to the C-12 carbon atom.

118. A -l2-keto-22-isoallospirostadiene having the formu a:

19. 2,3-epoxy-22-isoallospirostane compounds having the formula:

R o I 0 wherein R is an oxygen containing radical selected from thegroup which consists of keto and hydroxy radicals attached to the C-l2carbon atom.

20. 2,3-epoxy-12-keto-22-isoallospirostane having the formula:

21. 2,3-epoxy-12-hydroxy-22-isoallospirostane having the formula:

No references cited.

13. A COMPOUND SELECTED FROM THE GROUP WHICH CONSIST OF$2-22-ISOALLOSPIROSTENE COMPOUNDS HAVING THE FORMULA: